This invention relates generally to medical treatment methods. Specifically, the invention relates to methodology for the correction of defective chloride transport by increasing the salt and water flux in diseased tissues to levels closer to those found in normal tissues.
The invention discloses a method of activation of chloride transport in cystic fibrosis. Specifically, the methods of the present invention rely on the ability of benzimidazoles, e.g., omeprazole (PRILOSEC.TM.), to increase the activity of alternate chloride transport proteins in the lung. Omeprazole, a drug currently used for treatment of gastric ulcers, is known to function as a proton pump inhibitor ("PPI"). The present invention discloses that 2 it is also capable of activating chloride transport proteins on the surface of lung epithelial cells.
This treatment will reduce life-threatening complications frequently found in diseases such as cystic fibrosis. The method of increasing the permeability of epithelial cells to chloride ions comprises administering to a patient in need of such treatment a permeability enhancing amount of a composition comprising a specifically-defined nontoxic, benzimidazoles and benzimidazole derivatives.
Cystic fibrosis is a lethal disease affecting approximately one in 2,500 live Caucasian births and is the most common autosomal recessive disease in Caucasians. Patients with this disease have reduced chloride ion permeability in the secretory and absorptive cells of organs with epithelial cell linings, including the airways, pancreas, intestine, sweat glands and male genital tract. This, in turn, reduces the transport of water across the epithelia. The lungs and the GI tract are the predominant organ systems affected in this disease and the pathology is characterized by blocking of the respiratory and GI tracts with viscous mucus. The chloride impermeability in affected tissues is due to mutations in a specific chloride channel, the cystic fibrosis transmembrane conductance regulator protein (CFTR), which prevents normal passage of chloride ions through the cell membrane (Welsh et al., Neuron, 8:821-829 (1992)). There is no effective treatment for the disease, and therapeutic research is focused on gene therapy and/or activating the defective or other chloride channels in the cell membrane to normalize chloride permeability (Tizzano et al., J. Pediat., 120:337-349 (1992)). Damage to the lungs due to mucus blockage, frequent bacterial infections and inflammation is the primary cause of morbidity and mortality in CF patients and, although maintenance therapy has improved the quality of patients' lives, the median age at death is still only around 30 years.
The thick build-up of mucus deposits in the lungs leads to a higher than normal susceptibility towards fatal pulmonary infections. It is these infections, often of the Pseudomonas aeruginosa type, that are generally the causative agents of cystic fibrosis related death. At present, the established treatment protocols for cystic fibrosis involve treating these secondary infections with appropriate antibiotics, as well as adjusting diet and removing by physical means the deleterious build up of mucociliary secretions. Thus, considerable current effort is being devoted to developing treatments that operate by attacking the underlying cause of disease. Here, a variety of approaches have been explored. These range from attempts at gene therapy (incorporating the normal, wild-type cystic fibrosis gene into epithelia cells) to the administration of agents that restore electrolyte balance either by opening up other non-CFTR dependent chloride anion channels or by inhibiting cellular uptake of sodium cations. Unfortunately, the viability of this latter electrolyte balance restoration approach still remains limited.
The activation of the defective and/or alternative functioning chloride channels in cystic fibrosis epithelial cells in order to normalize their permeability to chloride is one of the primary therapeutic goals of the treatment of cystic fibrosis and has not yet been accomplished (Boat, T. F., Welsh, M. J. and Beaudet, A. L., "Cystic Fibrosis" in The Metabolic Basis of Inherited Disease, pp. 2649-2680 (Striver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D. eds.) McGraw-Hill, New York (1989)). Thus, there exists an urgent need for a treatment that increases the permeability of epithelial cells to chloride and thereby can be used to treat cystic fibrosis. Such a treatment would be most beneficial if it were nontoxic and nonirritating to the epithelial cell linings, yet allowed the restoration of the proper chloride equilibrium of the cells, as well as the clearing of existing mucus. The present invention satisfies this need by providing methods and compounds which can therapeutically relieve both the cause of the manifestations of cystic fibrosis, as well as the manifestations themselves.
Patents which discuss the use of benzimidazoles and benzimidazole derivative molecules include the following:
U.S. Pat. No. 5,607,69 1, Hale et al., issued Mar. 4, 1997, discloses methods of delivering pharmaceutical agents across membranes, including the skin layer or mucosal membranes of a patient. A pharmaceutical agent is covalently bonded to a chemical modifier, via a physiologically cleavable bond, such that the membrane transport and delivery of the agent is enhanced.
U.S. Pat. No. 5,576,338 Friesen et al., issued Nov. 19, 1996, describes bis(biaryl) compounds having activity as leukotriene biosynthesis inhibitors, to methods for their preparation, and to methods and pharmaceutical formulations for using these compounds in mammals (especially humans). Because of their activity as leukotriene biosynthesis inhibitors, the compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents including treatment of chronic lung diseases such as cystic fibrosis, bronchitis and other small- and large-airway diseases.
U.S. Pat. No. 5,603,943, Yanagawa, issued Feb. 18, 1997, discloses nasally administrable compositions comprising a physiologically active substance having a molecular weight of not more than 40,000 and a physiologically acceptable powdery or crystalline polyvalent metal carrier, wherein a physiologically effective amount of said active substance is dispersed homogeneously in and adsorbed homogeneously onto the metal carrier. Among the hundreds of actives disclosed is omeprazole.
U.S. Pat. No. 5,518,730, Fuisz, issued May 21, 1996, discloses biodegradable controlled release delivery systems using melt-spun biodegradable polymers as carriers for bio-effecting agents such as pharmaceutical actives. Non-limiting examples of specific bio-effecting agents which may be useful in the present invention includes omeprazole.
U.S. Pat. No. 5,066,652, Chiesi et al., issued Nov. 19, 1991, discloses a new class of inhibitors of gastric acidity consisting of benzimidazole derivatives of omeprazole. Pharmaceutical compositions of the invention can be administered by inhalatory or buccal routes, in any administration form. Inhalatory compositions can be solutions, suspensions, emulsions or powders of the active ingredient to be administered through an aerosol, or to be conditioned in aerosol bombs.
U.S. Pat. No. 5,250,527, Ife, issued Oct. 5, 1993, relates to the novel substituted benzimidazole derivatives and intermediates, which are inhibitors of potassium stimulated H+-K+ ATPase activity, the pharmaceutical compositions containing them and a method of inhibiting gastric acid secretion by administering them. A typical composition for inhalation comprises a solution, suspension or emulsion that may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
U.S. Pat. No. 4,255,431, Junggren et al., issued Mar. 10, 1981, is the original omeprazole patent which relates to compounds having valuable properties in affecting gastric acid secretion.